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Bin Hwangbo

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    ES07 - Thoracic Ultrasonography: Diagnosis and Staging (ID 10)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 4
    • Now Available
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      ES07.01 - Transthoracic Ultrasonography (Now Available) (ID 3186)

      13:30 - 15:00  |  Presenting Author(s): Najib M Rahman

      • Abstract
      • Presentation
      • Slides

      Abstract

      This presentation will review data on the utility of thoracic ultrasound in diagnosis, staging and subsequent management of malignant thoracic and pleural disease.

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      ES07.02 - Linear Endosonography (EBUS & EUS) (Now Available) (ID 3187)

      13:30 - 15:00  |  Presenting Author(s): Laurence M.M.J Crombag

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES07.03 - Radial Endosonography (Now Available) (ID 3188)

      13:30 - 15:00  |  Presenting Author(s): Laurence M.M.J Crombag

      • Abstract
      • Presentation
      • Slides

      Abstract

      Radial Endosonography

      Flexible bronchoscopy, with its attendant procedures, is a valuable tool for diagnosis and staging of patients with suspected lung cancer. The development of endobronchial ultrasound (EBUS) has extended the view of the bronchoscopist beyond the bronchial wall. Two types of EBUS exist. The curved linear (convex) probe EBUS and the radial probe EBUS. The convex ultrasound transducer is located at the tip of a flexible bronchoscope (linear scanning EBUS) and allows real-time sampling. This technique is mainly used for mediastinal nodal staging and assessment of centrally located lung tumours when lung cancer is known or suspected. The radial EBUS probe houses a rotating ultrasound transducer at the distal end which produces a high-resolution radial (360˚) ultrasound image of the airway wall and surrounding structures. This probe is inserted through the biopsy channel of a standard bronchoscope. In a lung cancer setting, this technique is used for evaluation of the depth of tumour invasion in the central airways enabling differentiation between early and invasive lung cancer and detection of peripheral pulmonary lesions (PPLs). Radial EBUS does not permit sampling in real-time such that sequential sampling with separate equipment is necessary. The current focus of this abstract is the role of radial EBUS for PPLs.

      With the increased use of chest CT-scans, the frequency of incidentally found PPLs has increased as well. Guidelines advise to evaluate and manage individuals with pulmonary nodules by estimating the probability of malignancy. The goal is to diagnose a malignancy promptly for timely treatment and to avoid invasive procedures and surgery in patients with benign lesions. Approaches to establish a tissue diagnosis include imaging-guided transthoracic and bronchoscopic sampling techniques.

      The sensitivity of traditional flexible bronchoscopy - with or without fluoroscopic guidance – for peripheral lesions in patients suspected of having lung cancer is suboptimal and is affected most by the size of the lesion (<2cm 34%; >2cm 63%).(1) For PPLs, the sensitivity of transthoracic needle aspiration (TTNA) is greater than that of bronchoscopy. In this setting, TTNA has an approximately 90% chance of providing confirmation of a diagnosis. However, CT-guided percutaneous TTNA has a considerable risk of pneumothorax.(1) This has led to the development of new modalities as radial EBUS, virtual bronchoscopy, electromagnetic navigation bronchoscopy and ultrathin bronchoscopes.

      In 2002, radial EBUS was first used to guide transbronchial lung biopsy (TBLB).(2) Numerous papers has been published since, reporting varying diagnostic performances of radial EBUS. Three systematic reviews and meta-analyses report a sensitivity of radial EBUS for diagnosis of peripheral lesions of 70% to 73%. Although there is considerable heterogeneity in lesion size, prevalence of malignancy, variable use of additional image guiding technology and reference standard in included studies.(3-5)

      The diagnostic yield of radial EBUS is significantly higher for lesion > 2 cm in size, malignant in nature and those associated with a bronchus sign on CT scan.(3-5) The diagnostic yield is also higher when the radial EBUS probe is in the center of the lesion opposed to being adjacent to it.(3) The diagnostic yield of radial EBUS does not exceed CT-guided percutaneous needle biopsy / aspiration. The major advantage of radial EBUS over a transthoracic approach is its safety profile (overall pneumothorax rate of just 1.0%)(4) and the ability to combine with staging procedures.

      In conclusion, to diagnose PPLs (not visible by bronchoscopy) radial EBUS is a safe and has a reasonably high diagnostic yield. Main limitations of the technique include operator dependence and the need for sequential sampling as radial EBUS does not allow real-time sampling.

      1. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e142S-e65S.

      2. Herth FJ, Ernst A, Becker HD. Endobronchial ultrasound-guided transbronchial lung biopsy in solitary pulmonary nodules and peripheral lesions. The European respiratory journal. 2002;20(4):972-

      3. Ali MS, Trick W, Mba BI, Mohananey D, Sethi J, Musani AI. Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis. Respirology (Carlton, Vic). 2017;22(3):443-53.

      4. Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. The European respiratory journal. 2011;37(4):902-10.

      5. Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of guided bronchoscopy for the evaluation of the pulmonary nodule. Chest. 2012;142(2):385-93.

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      ES07.04 - Predictive Molecular Testing on Small Biopsy Samples (Now Available) (ID 3189)

      13:30 - 15:00  |  Presenting Author(s): Christophe Dooms

      • Abstract
      • Presentation
      • Slides

      Abstract

      According to international guidelines for molecular testing as updated in 2018, any lung cancer sample (tissue biopsy or cytology) with adenocarcinoma or not-otherwise specified (NOS) histology and adequate tumor cellularity should be tested for routinely treatable mutations with a turnaround time of no more than 10 working days.1,2 Single gene testing or restricted hotspot testing methods were developed to screen for EGFR p.Leu858Arg mutations or deletions with the exon 19 in advanced stage non-small cell lung cancer. Next-generation sequencing (NGS) platforms have facilitated multigene mutational profiling using small amounts of nanograms (ng) of DNA, making the NGS technology attractive for and applicable to small biopsy and cytology specimens. NGS and especially targeted NGS panels were rapidly validated for small biopsy samples and implemented in diagnostic laboratories as they focus on hotspot regions and frequently altered genes with direct and known consequence on therapy.3,4 Compared to sequential single-gene testing, targeted NGS is considerably faster and more cost-effective.5

      There are however several barriers to universal broad biomarker testing. Despite most tests can be run on only small biopsy and cytology specimen, in real world testing rates are far from 100% (even for EGFR, ALK and ROS1 testing) and up to 25% of samples lack sufficient tumor material in small biopsies. Molecular testing accuracy depends on multiple factors that include overall tumor cellularity, method of fixation, tumor fraction of the sample, and the analytical sensitivity of the molecular testing platform used for the analysis. Pre-analytical strategies to improve testing success are: (1) work with dedicated interventionalists (e.g. radiology, pulmonology) to get sufficient tissue as one single pass is not enough, (2) work with dedicated pathologists to enhance quality control and reflex testing, and (3) consider ROSE.

      In a reference center with dedicated interventionalists, a dropout rate of 3.4% was observed either due to quantitatively insufficient tumor material or inadequate nucleic acid quality based on a series of 3,000 consecutive lung cancer cases that were sequenced.6 In a randomized trial comparing two different needle sizes and a turn-around team (interventional pulmonologist, pathologist, molecular biologist) using standard operating procedures, several conclusions could be drawn given a successful NGS testing rate for all clinically relevant genes in 96% of samples.7 Four needle passes were needed to obtain adequate material for molecular analysis. A tissue core was reported present in almost 70% of specimens for both needle types. Less than 3% of samples had tumor cellularity of <10%, and there was no significant difference in tumor cellularity between 19G and 22G needles. Both the tumor surface area measured and the amount of DNA extracted from the selected cell block were larger for the 19G compared to the 22G specimen, with a median tumor surface area of 4.91 mm2 vs 2.35 mm2 and median DNA extracted of 1150 ng vs 818 ng, respectively.

      There is a paucity of articles outlining best practice guidelines for immunocytochemistry. With proper optimization and rigorous quality control, high-quality staining can be achieved on cellblock and non-cellblock preparations.8 Cytology preparations that are non-formalin-fixed provide the best alternative source of well-preserved DNA.

      Cytology specimens allow for rapid on-site adequacy assessment (ROSE), which can ensure the collection of adequate and sufficient material for ancillary studies including immunohistochemistry and molecular testing. Although there are no universally accepted criteria for EBUS-TBNA lymph node adequacy, structured semi-quantitative scoring schemes for ROSE and diagnostic category assignments have been proposed. The decision of whether or not to provide ROSE for EBUS-TBNA procedures is largely institution dependent. Validation studies are essential with correct implementation of these pre-analytical factors for any molecular testing in cytologic samples.

      In conclusion, a single NGS panel test covering all clinical relevant markers is most tissue and cost efficient. Strategies to obtain a higher rate of successful testing, even on only small biopsy and cytology specimens should be considered whenever needed: reflex testing, dedicated interventionalists, and strong communication with all team members.

      References.

      1. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018 Mar;20(2):129-159.

      2. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology. Clinical Practice Guideline Update. J Clin Oncol. 2018 Mar 20;36(9):911-919.

      3. Bennett N, Farah C. Next-generation sequencing in clinical oncology: next steps towards clinical validation. Cancers 2014;6:2296-2312.

      4. Le Mercier M, De Nève N, Blanchard O, et al. Clinical application of targeted next generation sequencing for lung cancer patients. Belgian J Med Oncol 2015;27:2-8.

      5. Pennell N, Mutebi A, Zhou Z, et al. Economic impact of next-generation sequencing vs sequential single-gene testing modalities to detect genomic alterations in metastatic non-small cell lung cancer using a decision analytic model. J Clin Oncol 2018;36(15_suppl):9031-9031

      6. Volckmar AL, Leichsenring J, Kirchner M, et al. Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases. Int J Cancer. 2019 Jan 17. doi: 10.1002/ijc.32133. [Epub ahead of print]

      7. Dooms C, Vander Borght S, Yserbyt J, et al. A Randomized Clinical Trial of Flex 19G Needles versus 22G Needles for Endobronchial Ultrasonography in Suspected Lung Cancer. Respiration. 2018;96(3):275-282.

      8. Jain D, Nambirajan A, Borczuk A, et al; IASLC Pathology Committee. Immunocytochemistry for predictive biomarker testing in lung cancer cytology. Cancer Cytopathol. 2019 May;127(5):325-339.

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